Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors.
Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors.
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DOI：
10.1002/gcc.22438
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Kato M
中科院分区：
文献类型：
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作者：
Takahashi T;Elzawahry A;Mimaki S;Furukawa E;Nakatsuka R;Nakamura H;Nishigaki T;Serada S;Naka T;Hirota S;Shibata T;Tsuchihara K;Nishida T;Kato M
胃肠道间质瘤是最常见的消化道间叶肿瘤，由KIT的功能获得性突变驱动。尽管伊马替尼的益处已得到证实，但由于KIT的继发性耐药突变，接受伊马替尼治疗的患者中有一半在2年内显示疾病进展。目前尚不清楚基因组和转录组学特征如何在伊马替尼耐药性的获得过程中发生变化。在这里，我们对四种伊马替尼耐药细胞系和一种短暂暴露于伊马替尼的细胞系进行了外显子组测序和微阵列转录分析。我们还对临床肿瘤样品进行了外显子组测序。短暂暴露于伊马替尼的细胞系表现出很少的单核苷酸变异和拷贝数改变，但表现出与解毒相关的基因显著上调和参与细胞周期进程的基因下调。同时，耐药细胞系具有许多基因组变化：与解毒相关的基因扩增和具有细胞周期蛋白依赖性激酶活性的基因缺失。耐药样本中的一些变异可追溯到药物敏感样本，表明存在祖先亚群。这些亚群携带与细胞死亡相关的变异。具有促进细胞凋亡抗性的遗传改变的既存癌细胞可以作为具有关键突变（如继发性KIT突变）的癌细胞建立完全伊马替尼抗性的基础。© 2017 The Authors Genes，Chromosomes and Cancer由Wiley Periodicals，Inc.出版
Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract, driven by gain‐of‐function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib show disease progression within 2 years due to secondary resistance mutations in KIT. It remains unclear how the genomic and transcriptomic features change during the acquisition of imatinib resistance. Here, we performed exome sequencing and microarray transcription analysis for four imatinib‐resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of clinical tumor samples. The cell line briefly exposed to imatinib exhibited few single‐nucleotide variants and copy‐number alterations, but showed marked upregulation of genes related to detoxification and downregulation of genes involved in cell cycle progression. Meanwhile, resistant cell lines harbored numerous genomic changes: amplified genes related to detoxification and deleted genes with cyclin‐dependent kinase activity. Some variants in the resistant samples were traced back to the drug‐sensitive samples, indicating the presence of ancestral subpopulations. The subpopulations carried variants associated with cell death. Pre‐existing cancer cells with genetic alterations promoting apoptosis resistance may serve as a basis whereby cancer cells with critical mutations, such as secondary KIT mutations, can establish full imatinib resistance. © 2017 The Authors Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.